rs781734224

Variant names:

• chr11-22236263-A-G
• rs781734224
• NM_213599.3:c.749A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_213599.3(ANO5):​c.749A>G​(p.Tyr250Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,610,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene ANO5 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ANO5 NM_213599.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 2.91
• Publications: 4 publications found

Genes affected

ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

ANO5 Gene-Disease associations (from GenCC):

• gnathodiaphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2L

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Miyoshi muscular dystrophy 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for ANO5 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213599.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	NM_213599.3	MANE Select	c.749A>G	p.Tyr250Cys	missense	Exon 8 of 22	NP_998764.1	Q75V66
	ANO5	NM_001142649.2		c.746A>G	p.Tyr249Cys	missense	Exon 8 of 22	NP_001136121.1
	ANO5	NM_001410963.1		c.707A>G	p.Tyr236Cys	missense	Exon 7 of 21	NP_001397892.1	A0A804HL91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANO5	ENST00000324559.9	TSL:1 MANE Select	c.749A>G	p.Tyr250Cys	missense	Exon 8 of 22	ENSP00000315371.9	Q75V66
	ANO5	ENST00000682341.1		c.707A>G	p.Tyr236Cys	missense	Exon 7 of 21	ENSP00000508251.1	A0A804HL91
	ANO5	ENST00000684663.1		c.704A>G	p.Tyr235Cys	missense	Exon 7 of 21	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250906 AF XY: 0.0000295

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1458080 Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11 AN XY: 725586

African (AFR) AF: 0.000120 AC: 4 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1108890

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74306

African (AFR) AF: 0.0000965 AC: 4 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	not provided (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
-	1	-	Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	0.0040	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.059	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.87
MutPred		0.73		Loss of phosphorylation at Y250 (P = 0.0513)
MVP		0.76
MPC		0.43
ClinPred		0.96	D
GERP RS		1.7
Varity_R		0.89
gMVP		0.86
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781734224; hg19: chr11-22257809; COSMIC: COSV61089564;